Altered Response Pattern following AZD5582 Treatment of SIV-Infected, ART-Suppressed Rhesus Macaque Infants

• Type of Material: Article
• Authors: Katherine M Bricker, Emory University; Veronica Obregon-Perko, Emory University; Brianna Williams, Emory University; Danielle Oliver, Emory University; Ferzan Uddin, Emory University; Margaret Neja, Emory University; Louis Hopkins, Emory University; Amir Dashti, Emory University; Sherrie Jean, Emory University; Jennifer Wood, Emory University; Stephanie Ehnert, Emory University; Shan Liang, Emory University; Thomas Vanderford, Emory University; Gregory K Tharp, Emory University; Steven Bosinger, Emory University; Amanda P Schauer, University of North Carolina; Maud Mavigner, Emory University; Mackenzie L Cottrell, University of North Carolina; David Margolis, University of North Carolina; Richard M Dunham, University of North Carolina; Ann Chahroudi, Emory University
• Language: English
• Date: 2022-04-13
• Publisher: AMER SOC MICROBIOLOGY
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Bricker et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/jvi.01699-21
• Title of Journal or Parent Work: JOURNAL OF VIROLOGY
• Volume: 96
• Issue: 7
• Start Page: e0169921
• End Page: e0169921
• Grant/Funding Information: This work was conducted with federal funds from the U.S. National Institutes of Health (R01 AI133706 and UM1 AI164566). Research reported in this publication was also supported by the Emory CFAR Virology Core (P30 AI050409), the University of North Carolina at Chapel Hill CFAR (P30 AI050410), the Pediatrics/Winship Flow Cytometry Core of Winship Cancer Institute of Emory University, Children's Healthcare of Atlanta (P30 CA138292), and the Yerkes NPRC through the National Institutes of Health’s Office of the Director, Office of Research Infrastructure Programs, P51 OD011132, and U42 OD011023.
• Keywords: HIV cure; Science & Technology; RESERVOIR; Virology; HIV-1; SIV; Life Sciences & Biomedicine; pediatric HIV; HIV; NHP; CHALLENGES
• Research Categories: Biology, Microbiology; Health Sciences, Immunology

Abstract

The "shock and kill" strategy for HIV-1 cure incorporates latency-reversing agents (LRA) in combination with interventions that aid the host immune system in clearing virally reactivated cells. LRAs have not yet been investigated in pediatric clinical or preclinical studies. Here, we evaluated an inhibitor of apoptosis protein (IAP) inhibitor (IAPi), AZD5582, that activates the noncanonical NF-k B (ncNF-k B) signaling pathway to reverse latency. Ten weekly doses of AZD5582 were intravenously administered at 0.1 mg/kg to rhesus macaque (RM) infants orally infected with SIVmac251 at 4 weeks of age and treated with a triple ART regimen for over 1 year. During AZD5582 treatment, on-ART viremia above the limit of detection (LOD, 60 copies/mL) was observed in 5/8 infant RMs starting at 3 days post-dose 4 and peaking at 771 copies/mL. Of the 135 measurements during AZD5582 treatment in these 5 RM infants, only 8 were above the LOD (6%), lower than the 46% we have previously reported in adult RMs. Pharmacokinetic analysis of plasma AZD5582 levels revealed a lower Cmax in treated infants compared to adults (294 ng/mL versus 802 ng/mL). RNA-Sequencing of CD41 T cells comparing pre- and post-AZD5582 dosing showed many genes that were similarly upregulated in infants and adults, but the expression of key ncNF-k B genes, including NFKB2 and RELB, was significantly higher in adult RMs. Our results suggest that dosing modifications for this latency reversal approach may be necessary to maximize virus reactivation in the pediatric setting for successful "shock and kill" strategies.